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Antipsychotic drugs

2.
Antipsychotic drugs
• Antipsychotic drugs (also called neuroleptics or major
tranquilizers) are used primarily to treat schizophrenia (a
biologic illness), but they are also effective in other psychotic
states, including manic states with psychotic symptoms such as
grandiosity, paranoia, and hallucinations, and delusions.
• Antipsychotic drugs are not curative and do not eliminate
the chronic thought disorder, but they often decrease the
intensity of hallucinations and delusions and permit the
person with schizophrenia to function in a supportive
environment.

3.
History of antipsychotic drugs
• Antipsychotic drugs have been used in Western medicine
for more than 50 years.
• Chlorpromazine (1952) and Reserpine were the first drugs
found to be useful in schizophrenia.
• Tricyclic and MOA inhibitor antidepressant in 1957-58.
• Major novel antipsychotics are selective serotonin
reuptake inhibitor and it has been introduced in 1980s.
• Little attention was paid to Cade's report in 1949 that
Lithium could be used for excitement and mania: its
effective use started in the 1960s and now it has a unique
place in psychiatry.

6.
• Schizophrenia is a particular type of psychosis (that is, a mental
disorder caused by some inherent dysfunction of the brain). It
is characterized by delusions, hallucinations (often in the form
of voices), and thinking or speech disturbances. This mental
disorder is a common affliction, occurring in about 1 percent of
the population.
• Paranoid states with marked persecutory or other kinds of fixed
delusions (false beliefs) and loss of insight into the abnormality.
Psychoses - Schizophrenia and Paranoid states

7.
Psychoses - Affective disorders
• Mania- elation or irritable mood, reduced sleep, hyperactivity,
uncontrollable thought and speech, may be associated with
reckless or violent behaviour,
or
• Depression- sadness, loss of interest and pleasure,
worthlessness, guilt, physical and mental slowing, melancholia,
self-destructive ideation.
• A common form of mood disorders is bipolar disorder with
cyclically alternating manic and depressive phase. The relapsing
mood disorder may be unipolar (mania or depression) with
waxing and waning course.

12.
• First-generation antipsychotics
• The first-generation antipsychotic drugs (also called
conventional, typical, or traditional antipsychotics) are
competitive inhibitors at a variety of receptors, but their
antipsychotic effects reflect competitive blocking of D2
dopamine receptors.
• First-generation antipsychotics are more likely to be associated
with movement disorders, particularly for drugs that bind
tightly to dopaminergic neuroreceptors, such as haloperidol.
Pharmacotherapy of metal illness

13.
• Second-generation antipsychotic drugs
• The second generation antipsychotic drugs (also referred to as
“atypical” antipsychotics) have fewer extrapyramidal symptoms
(EPS) than the first-generation agents, but are associated with a
higher risk of metabolic side effects, such as diabetes,
hypercholesterolemia, and weight gain.
• The second-generation drugs appear to owe their unique
activity to blockade of both serotonin and dopamine receptors.
Pharmacotherapy of metal illness

15.
Pharmacology of chlorpromazine (CPZ)
• Mechanism of action
– Dopamine receptor–blocking
activity in the brain: All of the first
generation and most of the second-
generation antipsychotic drugs block
dopamine receptors in the brain and
the periphery (except clozapine-like
atypical).
– The clinical efficacy of the typical
antipsychotic drugs correlates
closely with their relative ability to
block D2 receptors in the
mesolimbic system of the brain.

16.
Pharmacology of chlorpromazine (CPZ)
• Mechanism of action
– The actions of the antipsychotic drugs are antagonized by
agents that raise synaptic dopamine concentrations (for
example, levodopa and amphetamines, bromocriptine) or
mimic dopamine at post-synaptic binding sites.
– Dopaminergic blockade pituitary locatotropes cause the
hyperprolactinemia, while that in CTZ is responsible for
antiemetic action.

17.
Pharmacology of chlorpromazine (CPZ)
• Chlorpromazine is a prototype agent for typical
antipsychotic agent.
• CNS: Effects differ in normal and psychotic individuals
• In normal individual CPZ
indifference to surroundings,
paucity of thought, psychomotor
slowing, emotional quietening,
reduction in initiative and
tendency to go off to sleep.
Spontaneous movements are
minimized but slurring of speech,
ataxia or motor incoordination
does not occur.
• In normal individuals CPZ
produces neuroleptic syndrome,
and is quite different from the
sedative action of barbiturates.
• In CPZ reduces irrational
behaviour, agitation and
aggressiveness and controls
psychotic symptomatology.
Disturbed thought and behaviour
are gradually normalized, anxiety
is relieved.
• Hyperactivity, hallucinations and
delusions are suppressed.
• All phenothiazines, thioxanthenes
and butyrophenones have the
same antipsychotic efficacy, but
potency differs in terms of
equieffective doses.

18.
Pharmacology of chlorpromazine (CPZ)
• CNS (in psychotic individuals):
– The sedative effect is produced promptly, while
antipsychotic effect takes weeks to develop. Moreover,
tolerance develops to the sedative but not to the
antipsychotic effect.
– Extrapyramidal motor disturbances are intimately linked to
the antipsychotic effect, but are more prominent in the high
potency compounds and least in thioridazine, clozapine and
other atypical antipsychotics.
– Chlorpromazine lowers seizure threshold and can precipitate
fits in untreated epileptics.
– Temperature control is knocked off at relatively higher doses
rendering the individual poikilothermic-body temperature
falls if surroundings are cold.

20.
Pharmacology of chlorpromazine (CPZ)
• Local anaesthetic: Chlorpromazine is as potent a local
anaesthetic as procaine. Because of its irritation action
CPZ is not used for this purposes and also its having
weaker/ no membrane stabilizing action.
• Cardiovascular System:
– Chlorpromazine has complex actions on the cardiovascular
system, directly affecting the heart and blood vessels and
indirectly acting through CNS and autonomic reflexes.
– Chlorpromazine and less potent antipsychotic agents, as well
as reserpine, risperidone, and olanzapine, can cause
orthostatic hypotension.
– Partial tolerance develops after chronic use. Reflex tachycardia
accompanies hypotension. Arrhythmia may occur in overdose
especially with thioridazine.

21.
Pharmacology of chlorpromazine (CPZ)
• Skeletal muscle: Neuroleptics have no effect on muscle
fibers or neuromuscular transmission. They reduce certain
types of spasticity : the site of action being in the basal
ganglia or medulla oblongata. Spinal reflex are not
affected.
• Kidney and Electrolyte Balance: Chlorpromazine may
have weak diuretic effects in animals and human beings
because of a depressant action on the secretion of
vasopressin (antidiuretic hormone), inhibition of
reabsorption of water and electrolytes by a direct action
on the renal tubule, or both.

22.
Pharmacology of chlorpromazine (CPZ)
• Endocrine:
– Neuroleptics consistently increase prolactin release by
blocking the inhibitory action of DA on pituitary lactotropes.
This may result in galactorrhoea and gynaecomastia. They
reduce gonadotropin secretion, but amenorrhoea and
infertility occur only occasionally.
– ACTH release in response to stress is diminished-
corticosteroid levels fail to increase under such
circumstances. Release of GH is also reduced but this is not
sufficient to cause growth retardation in children or to be
beneficial in acromegaly.
– Decreased release of ADH may result in an increase in urine
volume. A direct action on kidney tubules may add to it, but
Na+ excretion is not affected.

23.
Pharmacology of chlorpromazine (CPZ)
• Pharmacokinetics:
– Some antipsychotic drugs have erratic and unpredictable patterns
of absorption after oral administration.
– Parenteral (intramuscular) administration increases the
bioavailability of active drug four- to ten fold.
– Most antipsychotic drugs are highly lipophilic, highly membrane-
or protein-bound, and accumulate in the brain, lung, and other
tissues with a rich blood supply.
– They also enter the fetal circulation and breast milk. It is virtually
impossible and usually not necessary to remove these agents by
dialysis.
– Volume of distribution is large 20 L/kg and metabolized in liver by
CYP2D6; elimination t1/2 is variable (18-30 hr).
– Tolerance to the sedative and hypotensive action develops within
day or week.

25.
Distinctive features of neuroleptics
Typical antipsychotic
agent
Distinctive features of neuroleptics
Triflupromazine A aliphatic side phenothiazine; more potent than CPZ. Used mainly
as antiemetic
Thioridazine A low potency Phenothiazine having marked central
anticholinergic action. Risk of eye damage limits long-term use
Trifluoperazine,
fluphenazine
A high potency piperazine side chain of Phenothiazine. They have
minimum autonomic actions and cause jaundice (ADR).
Haloperidol It is a potent antipsychotic with pharmacological profile
resembling that of piperazine substituted phenothiazines.
Trifluperidol It is similar to but slightly more potent than haloperidol.
Penfluridol exceptionally long acting neuroleptic, recommended for chronic
schizophrenia
Flupenthixol Infrequently used now.
Pimozide It is a specific DA antagonist with little alpha adrenergic or
cholinergic blocking activity. It has been particularly used in Gilles
de la Tourette's syndrome and ticks.
Loxapine A dibenzoxazepine having CPZ like DA blocking and antipsychotic
activity

27.
second -generation antipsychotic agents
• Second generation antipsychotics have weak D2 blocking but
potent 5-HT2 antagonistic activity. Extrapyramidal side effects
are minimal, and they may improve the impaired cognitive
function in psychotics.

28.
Clozapine
• First atypical antipsychotic agent; Week D2 blocking action; few/no
extrapyramidal effects
• Both –ve and +ve symptoms of schizophrenia are improved; used as
a reserve drug in resistant schizophrenia.
• The differing pharmacological profile may be due to its relative
selectivity for D4 receptors (which are sparse in basal ganglia) and
additional 5-HT2 as well as a blockade.
• Clozapine is metabolized primarily by CYP3A4 with an average t1/2 of
12 hours. Its major limitation is higher incidence of agranulocytosis
(0.8%) and other blood dyscrasias; weekly monitoring of leucocyte
count is required. High dose can induce seizures even in
nonepileptics. Other side effects are sedation, unstable BP,
tachycardia, urinary incontinence, weight gain and precipitation of
diabetes.
Agranulocytosis is a rare condition that occurs when the bone marrow does not make enough neutrophils

29.
Risperidone
• Combination of D2 + 5-HT2 receptor blockade.
• In addition it has high affinity for α1, α2 and H1 receptors; blockade
of these may contribute to efficacy as well as side effects like
postural hypotension.
• Risperidone is more potent D2 blocker than clozapine;
extrapyramidal side effects are less only at low doses ( <6 mg/
day). Prolactin levels rise during risperidone therapy, but it is
less epileptogenic than clozapine.
• Caution: increased risk of stroke in the elderly.

30.
Olanzapine
(broader spectrum of efficacy covering schizo-affective disorders)
• resembles clozapine in blocking multiple monoaminergic (D2, 5-
HT2, α1, α2) as well as muscarinic and H1 receptors. Both
positive and negative symptoms of schizophrenia appear to be
benefited.
• A broader spectrum of efficacy covering schizo-affective
disorders, and it is approved for use in mania. Monotherapy
with olanzapine may be as effective as a combination of
lithium/valproate + benzodiazepines.
• Weaker D2 blockade results in few extrapyramidal side effects
and little rise in prolactin levels.
• Incidence of stroke may be increased in the elderly.
• Agranulocytosis has not been reported with olanzapine.
• Olanzapine is metabolized by CYP1A2 and glucuronyl
transferase. The t1/2 is 24-30 hours.

35.
Adverse events
• Extrapyramidal disturbances: Dose-limiting side effects.
– The inhibitory effects of dopaminergic neurons are normally balanced by
the excitatory actions of cholinergic neurons in the striatum. Blocking
dopamine receptors alters this balance, causing a relative excess of
cholinergic influence, which results in extrapyramidal motor effects.
– Parkinson-like symptoms of bradykinesia, rigidity, and tremor usually
occur within weeks to months of initiating treatment. Tardive dyskinesia,
which can be irreversible, may occur after months or years of treatment.
• Hypersensitivity reaction: Chlestatic jaundice, myocarditis,
agranulocytosis.
• Miscellaneous: Weight gain often occurs with long term
antipsychotic therapy; blood sugar and lipids may tend to rise. Risk
of worsening of diabetes and blue pigmentation of exposed skin,
and retinal degeneration.
Tardive dyskinesia is a disorder that involves involuntary movements, especially of the lower
face (tongue, lips, face, trunk, and extremities).

36.
Therapeutic uses
• Treatment of schizophrenia
• Prevention of severe nausea and vomiting
• Other uses:
– Treatment of mania, organic brain syndromes, anxiety.
– Chlorpromazine is used to treat intractable hiccups.
– Risperidone and haloperidol are also commonly prescribed for this
tic disorder. Also, risperidone and aripiprazole are now approved
for the management of the disruptive behavior and irritability
secondary to autism (is a disorder of neural development
characterized by impaired social interaction).